Method of treating bipolar i and ii disorders

ABSTRACT

The present invention relates to a method of treating a patient suffering from a disorder of the central nervous system associated with 5-HT 1A  receptor subtype, comprising as an active ingredient a carbostyril derivative or a salt thereof represented by the formula (1) 
     
       
         
         
             
             
         
       
     
     wherein the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single or a double bond.

This is a division of application Ser. No. 10/876,605, filed Jun. 28,2004, which is a division of application Ser. No. 10/055,915, filed Jan.28, 2002, now U.S. Pat. No. 7,053,092, which claims benefit of U.S.Provisional Application No. 60/331,370, filed Jan. 29, 2001, all ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a method of treating a patientsuffering from a-disorder of the central nervous system associated withthe 5-HT_(1A) receptor subtype. The active ingredient comprise acarbostyril derivative or a salt thereof.

Related Art

U.S. Pat. No. 5,006,528; European Patent No. 367,141 and Japanese PatentKokai (Laid-open) 7-304,740 (1995) contain the same chemical structuralformula as the carbostyril derivatives in the present invention, andtheir pharmacological properties are beneficial drug treatments forschizophrenia.

Carbostyril compounds, as well as those disclosed in Japanese PatentKokai (Laid-open) 9-301,867 (1997) are useful for the treatment ofanxiety.

The carbostyril derivatives disclosed in European Patent No. 226,441have the genus of the carbostyril derivatives in the present invention,and they are useful for the treatment of hypoxia.

In addition to the above, the carbostyril derivatives disclosed in U.S.Pat. No. 4,734,416; Canadian Patent No. 1,117,110; British Patent No.2,017,701; German Patent Nos. 2,912,105 and 2,953,723; Japanese PatentKokai(Laid-open)Nos. 54-130,587 (1979), 55-127,371 (1980) and 62-149,664(1987) have the genus of the carbostyril derivatives in the presentinvention, and they have antihistaminic activities and central nervouscontrolling activities.

It is reported that aripiprazole(7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril,also known as, OPC-14597, BMS-337,039 and OPS-31) binds with highaffinity to dopamine D₂ receptors and with moderate affinity to dopamineD₃ and 5-HT₇ receptors (Masashi Sasa et al., CNS Drug Reviews, Vol. 3,No. 1, pp. 24-33).

Further, it is reported that aripiprazole possesses presynapticdopaminergic autoreceptor agonistic activity, postsynaptic D₂ receptorantagonistic activity, and D₂ receptor partial agonistic activity (T.Kikuchi, K. Tottori, Y. Uwahodo, T. Hirose, T. Miwa, Y. Oshiro and S.Morita: J. Pharmacol. Exp. Ther., Vol. 274, pp. 329, (1995); T. Inoue,M. Domae, K. Yamada and T. Furukawa: J. Pharmacol. Exp. Ther., Vol. 277,pp. 137, (1996)).

However, it has not been reported that compounds in the presentinvention have agonistic activity at 5-HT_(1A) receptor subtype.

It has been reported that therapeutic interventions using 5-HT_(1A)receptor ligands may be useful drug treatments for alcohol abuse (MarkKleven et al., European Journal of Pharmacology, Vol. 281, (1995) pp.219-228).

It is also reported that 5-HT_(1A) agonist drugs may be useful for thetreatment and/or prophylaxis of disorders associated with neuronaldegeneration resulting from ischemic events in mammals (U.S. Pat. No.5,162,375).

It is also reported that 5-HT_(1A) receptor hypersensitivity could bethe biological basis for the increased frequency of migraine attack instressful and anxious conditions (Massimo Leone et al., Neuro Report,Vol. 9, pp. 2605-2608(1998)).

It has recently been reported that(-)—(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxidemonohydrochrolide (BAY-3702), a 5-HT_(1A) receptor agonist, hasneuroprotective, anxiolytic- and antidepressant- like effects in animalmodels (Jean De Vry et al., European Journal of Pharmacology, Vol. 357,(1998), pp. 1-8).

It is also reported that 5-HT _(1A) receptor agonists appear to be broadspectrum antiemetic agents (Mary C. Wolff et al., European Journal ofPharmacology, Vol. 340, (1997), pp. 217-220; AB Alfieri et al., BritishJournal of Cancer, (1995), Vol. 72, pp. 1013-1015; Mary C. Wolff et al.,Pharmacology Biochemistry and Behavior, 1995, Vol. 52, No. 3, pp.571-575; James B. Lucot, European Journal of Pharmacology, 1997, Vol.253. pp. 53-60).

Serotonin plays a role in several neurological and psychiatricdisorders, including Alzheimer's disease, depression, nausea andvomiting, eating disorders, and migraine. (See Rasmussen et al.,“Chapter 1. Recent Progress in Serotonin 5HT_(1A) Receptor Modulators”,in Annual Reports in Medicinal Chemistry, Vol. 30, Section I, pp. 1-9,1995, Academic Press, Inc.). WO 00/16777 discloses that a 5HT_(1A)receptor agonist, buspirone is efficacious in treating a variety ofsymptoms associated with ADHD, and that combined use of a D2 receptoragonist and 5-HT_(1A) agonist provides effective treatments for ADHD andParkinson's disease.

5HT_(1A) agonists are effective in the treatment of cognitive impairmentin Alzheimer's disease, Parkinson's disease or senile dementia, U.S.Pat. No. 5,824,680 discloses that a 5-HT_(1A) agonist, ipsapirone, iseffective in treating Alzheimer's disease by improving memory. U.S. Pat.No. 4,687,772 describes that a 5-HT_(1A) partial agonist, buspirone, isuseful for improving short term memory in patients in need of treatment.WO 93/04681 discloses that use of 5-HT_(1A) partial agonists have beenused for the treatment or prevention of cognitive disorders associatedwith Alzheimer's disease, Parkinson's disease or senile dementia.

5HT_(1A) agonists are also effective in the treatment of depression.U.S. Pat. No. 4,771,053 describes that a 5-HT_(1A) receptor partialagonist, gepirone, is useful in alleviation of certain primarydepressive disorders, such as severe depression, endogenous depression,major depression with melancholia, and atypical depression. WO 01/52855discloses that the combined use of the 5-HT_(1A) receptor partialagonist gepirone with an antidepressant can effectively treatdepression.

The 5-HT_(1A) receptor partial agonist buspirone alleviates motordisorders such as neuroleptic induced parkinsonism and extrapyramidalsymptoms. These observations are disclosed in U.S. Pat. No. 4,438,119.Furthermore 5-HT_(1A) agonists reverse neuroleptic-induced catalepsy inrodents, which mimic movement impairments observed in Parkinson'sdisease (Mark J. Millan, .Journal of Pharmacology and ExperimentalTherapeutics, 2000, Vol. 295. p853-861). Thus, aripiprazole can be usedto manage psychosis in geriatric patients, Alzheimer's disease,Parkinson's disease or senile dementia, since it possesses potent,partial agonistic activities at D₂ and 5-HT_(1A) receptors. In addition,these patients might not experience extrapyramidal symptoms due to thisproperty of aripiprazole.

Heretofore, schizophrenia is understood to be caused by hyperactivity inthe brain dopaminergic system. For this reason, some drugs weredeveloped with strong dopaminergic receptor blocking activity. Thesetypical antipsychotic drugs are effective in the treatments for thepositive symptoms of schizophrenia, which include hallucinations,delusions and the like. During the last decade, a variety of atypicalanti-psychotic drugs have been developed, which include clozapine,risperidone, olanzapine, quetiapine. These drugs have lessextrapyramidal side effects, and have other activities in addition totheir DA-receptor blocking activities. In contrast to typicalanti-psychotic drugs, such as chlorpromazine, haloperidol, etc., it isreported that atypical antipsychotic drugs are more effective againstthe negative symptoms and cognitive impairments associated withschizophrenia than typical antipsychotic drugs, and atypicalantipsychotic drugs also have less extrapyramidal side effects (S.Miyamoto, G. E. Duncan, R. B. Mailman and J. A. Lieberman: CurrentOpinion in CPNS Investigational Drugs, Vol. 2, pp. 25, (2000)). However,even though atypical antipsychotic drugs provide a suitablepharmacotherapy for schizophrenia, certain patients are resistant to theantipsychotic therapies of these drugs. These patients may either notrespond or may become refractory (i.e. may feel more anxious, depressedor cognitive dysfunction) in response to antipsychotic therapy. Thesetreatment-resistant patients pose a problem for how a physician mayprovide an appropriate therapy.

At present, a number of treatment-resistant and treatment-refractoryschizophrenic patients display symptoms that do not respond adequatelyto a variety of known effective classes and doses of typical or atypicalantipsychotic drugs. Furthermore, these patients may also be inveterateschizophrenia or chronic schizophrenics who are often repeatedlyadmitted to and discharged from hospitals (R. R. Conely and R. W.Buchanan: Schizophr. Bull., Vol. 23, pp. 663, (1997)).

Symptoms of patients corresponding to treatment-resistant andtreatment-refractory schizophrenics involve not only the positivesymptoms, but also the negative symptoms and emotional disorders, aswell as cognitive impairments (i.e., cognitive dysfunction or cognitivedisturbances) (K. Akiyama and S. Watanabe: Jpn. J. Clin.Psychopharmacol., Vol. 3, pp. 423, (2000)).

Cognitive impairment exists separately from the psychic symptoms in aschizophrenic individual. Thus, medical treatment is therefore quiteimportant, because the cognitive impairment may disturb the sociallyadaptable behavior of these individuals (C. Hagger, P. Buckley, J. T.Kenny, L. Friedman, D. Ubogy and H. Y. Meltzer: Biol. Psychiatry, Vol.34, pp. 702, (1993); T. Sharma and D. Mockler: J. Clin.Psycho-pharmacol., Vol. 18, (Suppl. 1), pp. 128, (1998)).

At present, clozapine is an antipsychotic drug that is effective againsttreatment-resistant schizophrenia. Clozapine (marketed under the name ofClozaril) was approved in 1990 by FDA for the treatment and managementof severely ill schizophrenics who failed to respond adequately tostandard antipsychotic therapy (M. W. Jann: Pharmacotherapy, Vol. 11,pp. 179, (1991)). Clozapine has been reported to be effective againstcognitive impairments in treatment-resistant schizophrenics (C. Hagger,P. Buckley, J. T. Kenny, L. Friedman, D. Ubogy and H. Y. Meltzer: Biol.Psychiatry, Vol. 34, pp. 702, (1993); M. A. Lee, P. A. Thompson and H.Y. Meltzer: J. Clin. Psychiatry, Vol. 55 (Suppl. B), pp. 82, (1994) ; D.E. M. Fujii, I. Ahmed, M. Jokumsen and J. M. Compton: J. NeuropsychiatryClin. Neurosci., Vol. 9, pp. 240, (1997)). For example, it is reportedthat clozapine improves cognitive impairments in attention, responsetime, fluent-speech, etc. in treatment-resistant schizophrenics (M. A.Lee, P. A. Thompson and H. Y. Meltzer: J. Clin. Psychiatry, Vol. 55(Suppl. B), pp. 82, (1994)). It has been also reported that clozapineprovides effective improvements in cognitive impairments in an objectiveevaluation scale of the Wechsler Adult Intelligence Scale-Revised FullScale (D. E. M. Fujii, I. Ahmed, M. Jokumsen and J. M. Compton: J.Neuropsychiatry Clin. Neurosci., Vol. 9, pp. 240, (1997)).

The 5-HT_(1A) receptor has been demonstrated to play a role in thetherapeutic efficacy of clozapine against treatment-resistantschizophrenia and cognitive impairments. This relation ship was revealedby a binding experiment using human the 5-HT_(1A) receptors (S. L. Masonand G. P. Reynolds: Eur. J. Pharmacol., Vol. 221, pp. 397, (1992)).Further, in accordance with progress in molecular pharmacology, it isclearly understood that 5-HT_(1A) receptor agonistic activity or5-HT_(1A) receptor partial agonistic activity plays an important role intreatment-resistant schizophrenia and cognitive impairments (A.Newman-Tancredi, C. Chaput, L. Verriele and M. J. Millan:Neuropharmacology, Vol. 35, pp. 119, (1996)). Additionally, it wasreported that the number of 5-HT_(1A) receptor is increased in theprefrontal cortex of chronic schizophrenics who were classifiedtreatment-resistant. This observation was explained by a compensatoryprocess where by the manifestation of severe symptoms of chronicschizophrenia are a result of impaired neuronal function mediated byhypofunctional 5-HT_(1A) receptors (T. Hashimoto, N. Kitamura, Y.Kajimoto, Y. Shirai, O. Shirakawa, T. Mita, N. Nishino and C. Tanaka:Psycho-pharmacology, Vol. 112, pp. S35, (1993)). Therefore, a loweringin neuronal transmission mediated through 5-HT_(1A) receptors isexpected in treatment-resistant schizophrenics. Thus the clinicalefficacy of clozapine may be related to its partial agonist efficacy atthe 5-HT_(1A) receptors (A. Newman-Tancredi, C. Chaput, L. Verriele andM. J. Millan: Neuropharmacology, Vol. 35, pp. 119, (1996)). 5-HT_(1A)receptor agonistic activity may be related to the clinical effects ofclozapine, and this hypothesis is supported by a positron emissiontomography study in primates which showed that clozapine interacts withbrain 5-HT_(1A) receptors at a therapeutically effective dose (Y. H.Chou, C. Halldin and L. Farde: Int. J. Neuropsycho-pharmacol., Vol. 4(Suppl. 3), pp. S130, (2000)). Furthermore tandospirone, which is knownas a selective 5-HT_(1A) receptor agonist, improved cognitiveimpairments in chronic schizophrenic patients (T. Sumiyoshi, M. Matsui,I. Yamashita, S. Nohara, T. Uehara, M. Kurachi and H. Y. Meltzer: J.Clin. Pharmacol., Vol. 20, pp. 386, (2000)). While, in animal tests, allreports do not always suggest that 5-HT_(1A) receptor agonist activitymay be related to cognitive impairment, however, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), which is known as a selective 5-HT_(1A)receptor agonist, improves learning and memory impairments induced byscopolamine known as a muscarinic receptor antagonist, suggesting arelationship between 5-HT_(1A) receptor agonistic activity andimprovements in cognitive impairments (M. Carli, P. Bonalumi, R.Samanin: Eur. J. Neurosci., Vol. 10, pp. 221, (1998); A. Meneses and E.Hong: Neurobiol. Learn. Mem., Vol. 71, pp. 207, (1999)).

Atypical antipsychotic drugs, such as risperidone and olanzapine, weremarketed after clozapine, and it is reported that these drugs improvetreatment-resistant schizophrenia or cognitive impairments intreatment-resistant schizophrenics (M. F. Green, B. D. Marshall, Jr., W.C. Wirshing, D. Ames, S. R. Marder, S. McGurck, R. S. Kern and J. Mintz:Am. J. Psychiatry, Vol. 154, pp. 799, (1997); G. Bondolifi, H. Dufour,M. Patris, J. P. May, U. Billeter, C. B. Eap .and P. Baumann, on behalfof the risperidone Study Group: Am. J. Psychiatry, Vol. 155, pp. 499,(1998); A. Breier, S. H. Hamilton: Biol. Psychiatry, Vol. 45, pp. 403,(1999)).

In contrast to reports that clozapine was moderately effective againsttreatment-resistant schizophrenia, risperidone and olanzapine were notconsistently superior to typical antipsychotic drugs in theireffectiveness against treatment-resistant schizophrenia. Thus,risperidone and olanzapine bind with lower affinity to human 5-HT_(1A)receptors (S. Miyamoto, G. E. Duncan, R. B. Mailman and J. A. Lieberman:Current Opinion in CPNS Investigational Drugs, Vol. 2, pp. 25, (2000)),and as such these drugs can not clearly perform activities through human5-HT_(1A) receptors at clinical effective doses.

Therefore, at present, it is understood that clozapine is effectiveagainst treatment-resistant schizophrenia (D. W. Bradford, M. H. Chakos,B. B. Sheitman, J. A. Lieberman: Psychiatry Annals, Vol. 28, pp. 618,(1998); A. Inagaki: Jpn. J. Clin. Psychopharmacol Vol. 3, pp. 787,(2000)).

As explained above, 5-HT _(1A) receptor agonistic activity is importantfor improving treatment-resistant schizophrenia or cognitive impairmentcaused by treatment-resistant schizophrenia. Clozapine is effectiveagainst treatment-resistant schizophrenia, however, its use is limiteddue to its severe side-effect of producing agranulocytosis whichrequires patients to undergo periodical blood tests. Under thesecircumstances, the development of a safe anti-psychotic drug withpotent, full or partial agonist activity at 5-HT_(1A) receptors isearnestly desired.

The carbostyril compound in the present invention binds with highaffinity and displays a potent, partial agonist activity at the5-HT_(1A) receptors and it has higher intrinsic activity (about 68%) ascompared with that of clozapine. Therefore, the compound in the presentinvention has a 5-HT_(1A) receptor agonistic activity that is morepotent than the agonistic activity of clozapine. Thus, the presentcarbostyril compound may represent a more potent and highly safe drugfor curing treatment-resistant schizophrenia, cognitive impairmentscaused by treatment-resistant schizophrenia, inveterate schizophrenia,cognitive impairments caused by inveterate schizophrenia, chronicschizophrenia, cognitive impairments caused by chronic schizophrenia andthe like, as compared with other currently available pharmacotherapeutictreatments. That is, the compound in the present invention may prove tobe a potent and safer drug therapy for treatment-resistantschizophrenia, cognitive impairments caused by treatment-resistantschizophrenia, inveterate schizophrenia, cognitive impairments caused byinveterate schizophrenia, chronic schizophrenia, or cognitiveimpairments caused by chronic schizophrenia, etc., which fail to respondadequately to currently available antipsychotic drugs such aschlorpromazine, haloperidol, sulpiride, fluphenazine, perphenazine,thioridazine, pimozide, zotepine, risperidone, olanzapine, quetiapine,amisulpride, etc.

In particular, the carbostyril compound in the present invention may bea potent and highly safe drug therapy against treatment-resistantschizophrenia, cognitive impairments caused by treatment-resistantschizophrenia, inveterate schizophrenia, cognitive impairments caused byinveterate schizophrenia, chronic schizophrenia or cognitive impairmentscaused by chronic schizophrenia, etc. which fail to respond adequatelyto both of 1 to 3 typical antipsychotic drugs selected from the groupconsisting of chlorpromazine, haloperidol and perphenazine, and oneatypical antipsychotic drug selected from the group consisting ofrisperidone, olanzapine, quetiapine and amisulpride.

Moreover, the compound in the present invention may be a potent andhighly safe drug therapy against treatment-resistant schizophrenia,cognitive impairments caused by treatment-resistant schizophrenia,inveterate schizophrenia, cognitive impairment caused by inveterateschizophrenia, chronic schizophrenia or cognitive impairment caused bychronic schizophrenia, etc. which fail to respond adequately to both of2 typical antipsychotic drugs selected from the group consisting ofchlorpromazine, haloperidol and perphenazine, and one atypicalantipsychotic drug selected from the group consisting of risperidone,olanzapine, quetiapine and amisulpride.

Moreover, the compound in the present invention may be a potent andhighly safe drug therapy against treatment-resistant schizophrenia,cognitive impairments caused by treatment-resistant schizophrenia,inveterate schizophrenia, cognitive impairments caused by inveterateschizophrenia, chronic schizophrenia, or cognitive impairment caused bychronic schizophrenia, etc. which fail to respond adequately to both of1 to 2 typical antipsychotic drugs selected from the group consisting ofchlorpromazine and haloperidol, and one atypical antipsychotic drugselected from the group consisting of risperidone, olanzapine,quetiapine and amisulpride.

Moreover, the compound in the present invention may be a potent andhighly safe drug therapy against treatment-resistant schizophrenia,cognitive impairments caused by treatment-resistant schizophrenia,inveterate schizophrenia, cognitive impairment caused by inveterateschizophrenia, chronic schizophrenia or cognitive impairment caused bychronic schizophrenia, etc. which fail to respond adequately to both of2 typical antipsychotic drugs selected from the group consisting ofchlorpromazine and haloperidol, and one atypical antipsychotic drugselected from the group consisting of risperidone, olanzapine,quetiapine and amisulpride.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method of treatinga patient suffering from a disorder of the central nervous systemassociated with the 5-HT_(1A).receptor subtype.

DETAILED DESCRIPTION OF THE INVENTION

As the 5-HT_(1A) receptor subtype agonist compound for use in accordancewith the present invention, carbostyril derivatives represented by thefollowing formula (1) are used:

wherein the carbon-carbon bond between 3- and 4-positions in thecarbostyril skeleton is a single or a double bond.

The compounds of the forgoing general formula (1) are known compounds,which are disclosed in publication such as U.S. Pat. No. 5,006,528 orwhich can be readily prepared by the processes described in the abovepublication.

The carbostyril derivative represented by the formula (1) in the presentinvention can easily be converted into its acid-addition salt byreacting it with a pharmaceutically acceptable acid. Examples of suchacid include inorganic acids, such as hydrochloric acid, sulfuric acid,phosphoric acid, hydrobromic acid and the like; organic acids, such asoxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid,citric acid, benzoic acid and the like.

The solvent of solvates is a solvent conventionally used inrecrystallization. Examples of solvates include hemihydrates, hydrates,and alcoholates, such as ethanolates, methanolates, isopropanolates andthe like.

The desired compounds, prepared by the reactions mentioned above, caneasily be isolated and purified by usual separation procedures such assolvent extraction, dilution, recrystallization, column chromatography,preparative thin layer chromatography and the like.

The potent, partial 5-HT_(1A) receptor agonist in the present inventionis useful for various disorders of the central nervous system associatedwith the 5-HT_(1A) receptor subtype that induces bipolar disorders, suchas bipolar I disorder with most recent hypomanic, manic, mixed,depressed or unspecified episode; bipolar II disorder with recurrentmajor depressive episodes with hypomanic episodes, and cyclothymicdisorder; depression, such as endogenous depression, major depression,melancholia, and treatment-resistant depression; panic disorder;obsessive compulsive disorder (OCD); sleep disorders; sexualdysfunction; alcohol abuse and drug addiction; cognitive impairment;neurodegenerative diseases, such as Alzheimer's disease, Parkinson'sdisease and the like, cognitive impairments caused by neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease and relateddisorders; emesis; motion sickness; obesity; migraine; autism; Down'ssyndrome; attention-deficit hyperactivity disorder (ADHD);treatment-resistant, inveterate or chronic schizophrenia, (which fail torespond adequately to currently available antipsychotic drugs);cognitive impairments caused by treatment-resistant schizophrenia,inveterate schizophrenia or chronic schizophrenia and the like.

Compounds of the present invention may be suitably prepared intopharmaceutically acceptable formulations (see U.S. Pat. No. 5,006,528,European Patent No. 367,141 and Japanese Kokai (Laid-open) 7-304,740(1995), and Japanese Patent Application No. 2000-194976 incorporated byreference herein).

The dosage of these pharmaceutical preparations of the invention may beselected appropriately depending on the method of administration, thepatient's age, sex and other factors, severity of the disease and otherfactors. Generally, however, the daily dose of the active ingredientcompound is preferably within the range of about 0.0001 to about 50 mgper kilogram of body weight. It is desirable that the active ingredientcompound be contained in each unit dosage form in an amount of about0.001 to about 1,000 mg, particularly 0.01 to 100 mg, more particularly0.1 to 50 mg, yet more particularly 1 mg to 20 mg.

PHARMACOLOGICAL TESTS 1. Materials and Methods 1.1 Test Compound

7-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril(aripiprazole) was used as test compound.

1.2 Reference Compounds

Serotonin (5-HT) and WAY-100635(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridimyl)-cyclohexanecarboxamide,a 5-HT_(1A) receptor antagonist, manufactured by RBI (Natick, Mass.)were used as reference compounds.

1.3 Vehicle

Dimethyl sulfoxide (DMSO) manufactured by Sigma Chemical Co. (St. Louis,Mo.) was used as vehicle.

1.4 Preparation of Test and Reference Compounds

Test compound was dissolved in 100% dimethyl sulfoxide (DMSO) to yield100 μM stock solutions (final concentration of DMSO in all tubescontaining test compound was 1%, v/v). All other reference compoundswere prepared by the same method using double-distilled water ratherthan DMSO.

1.5 Experimental Procedure for the [³⁵S]GTP_(γ)S Binding Assay

Test and reference compounds were studied in triplicate at 10 differentconcentrations (0.01, 0.1, 1, 5, 10, 50, 100, 1000, 10000 and 50000 nM)for their effects upon basal [³⁵S]GTP_(γ)S binding to h5-HT_(1A) CHOcell membranes. Reactions were performed in 5 ml glass test tubescontaining 8 μl of test/reference drug mixed with 792 μl of buffer (25mM Tris HCl, 50 mM NaCl, 5 mM MgCl₂, 0.1 mM EGTA, pH=7.4) containing GDP(1 μM), [³⁵S]GTP_(γ)S (0.1 nM) and h5-HT_(1A) CHO cell membranes (10 μgprotein/reaction; NEN Life Science Products, Boston, Mass.; catalog#CRM035, lot #501-60024, GenBank #X13556). Reactions proceeded for 60min at room temperature and were terminated by rapid filtration throughWhatman GF/B filter paper, using a Brandel harvester and 4×3 ml ice-coldbuffer washes. ³⁵S radio-activity bound to the filter paper was measuredusing liquid scintillation counting (1272 Clinigamma, LKB/Wallach).

1.6 Experimental Procedure to Determine the Binding Affinity of Testcompound (aripiprazole) at the h5-HT_(1A) Receptor

Test compound was studied in triplicate at 10 different concentrations(0.01, 0.1, 1, 10, 50, 100, 500, 1000, 5000 and 10000 nM) to determineits displacement of [³H] 8-OH-DPAT (1 nM; NEN Life Sciences; catalog#NET 929, lot #3406035, Specific Activity=124.9 Ci/mmol) binding toh5-HT_(1A) receptors in CHO cell membranes (15-20 μg protein; NEN LifeScience Products, catalog #CRM035, lot #501-60024). Membranes (396 μl)were incubated in 5 ml glass tubes containing [³H] 8-OH-DPAT (396 μl),test compound or vehicle (8 μl) and buffer A (50 mM Tris.HCl, 10 mMMgSO₄, 0.5 mM EDTA, 0.1% (w/v) ascorbic acid, pH=7.4). All assaysproceeded for 60 min at room temperature and were terminated by rapidfiltration through Whatman GF/B filter paper (presoaked in buffer B; 50mM Tris.HCl, pH=7.4), using a Brandel harvester and 4×1 ml ice-coldwashes with buffer B. Non-specific binding was determined in thepresence of 10 μM (+) 8-OH-DPAT.

1.7 Parameters Determined

Serotonin (5-HT) is a full 5-HT_(1A) receptor agonist which stimulatesincreases in basal [³⁵S]GTP_(γ)S binding to h5-HT_(1A) receptors inrecombinant CHO cell membranes. Test compound was studied at 10concentrations to determine their effects upon basal [³⁵S]GTP_(γ)Sbinding relative to that produced by 10 μM 5-HT. The relative potency(EC₅₀, 95% confidence interval) and intrinsic agonist activity (% ofE_(max) for 10 μM 5-HT) was calculated for each compound by computerizednon-linear regression analysis of complete concentration-effect data.The binding affinity of test compound at the h5-HT_(1A) receptor wasdetermined by its ability to prevent [³H] 8-OH-DPAT binding to CHO cellmembranes that express this receptor. Non-linear regression analysis ofthe competition binding data was used to calculate an inhibitionconstant (IC₅₀, 95% confidence interval), which is the concentration oftest compound that occupies half of the h5-HT_(1A) sites specificallybound by [³H] 8-OH-DPAT. The affinity of h5-HT_(1A) receptors for testcompound (Ki, 95% confidence interval) was calculated by the equation,Ki=(IC₅₀)/(1+([[³H] 8-OH-DPAT]/Kd), where the Kd for [³H] 8-OH-DPAT ath5-HT_(1A)=0.69 nM (NEN Life Sciences). All estimates of drug bindingaffinity, potency and intrinsic efficacy at the h5-HT_(1A) receptor werecalculated using GraphPad Prism version 3.00 for Windows (GraphPadSoftware, San Diego, Calif.).

2. Results

Test compound and 5-HT produced concentration-dependent increases abovebasal [³⁵S]GTP_(γ)S binding. 1% DMSO tested alone had no effect uponbasal or drug-induced [³⁵S]GTP_(γ)S binding.

Test compound (EC₅₀=2.12 nM) , 5-HT (EC₅₀−3.67 nM), potently stimulated,basal [³⁵S]GTP_(γ)S binding. Potency and intrinsic agonist efficacyestimates were derived by non-linear regression analysis withcorrelation coefficients (r²)>0.98 in each case (Table 1). Test compoundexerted partial agonist efficacies in the 65-70% range. WAY-100635produced no significant change (unpaired Student's t-test) in basal[³⁵S]GTP_(γ)S binding at all concentrations tested (Table 1). WAY-100635did, however, completely inhibit the effects of 5-HT and test compoundupon [³⁵S]GTP_(γ)S binding to h5-HT_(1A) receptors in CHO cell membranes(Table 2). Tables 1 and 2 are shown below.

Test compound demonstrated high affinity binding to h5-HT_(1A) receptorsin CHO cell membranes (IC₅₀=4.03 nM, 95% confidence interval=2.67 to6.08 nM; Ki=1.65 nM, 95% confidence interval=1.09 to 2.48 nM).

TABLE 1 Potency (EC₅₀) and Intrinsic Agonist Efficacy (E_(max)) of Testcompound and Reference Drugs in a h5-HT_(1A) [³⁵S]GTP_(γ)S CHO-cellMembrane Binding Assay. EC₅₀, nM E_(max) Goodness Drug (95% ConfidenceInterval) (% ± SEM) of Fit (r²) Test Compound 2.12 68.13 ± 3.16 0.986(0.87 to 5.16) 5-HT 3.67 98.35 ± 4.47 0.986 (1.56 to 8.63) WAY-100635 —— —

TABLE 2 Inhibitory Potency (IC₅₀) of WAY-100635 versus 1 μMConcentration of 5-HT and Test compound in a h5-HT_(1A) [³⁵S]GTP_(γ)SCHO-cell Membrane Binding Assay. WAY-100635 Inhibition Potency, IC₅₀, nMGoodness Drug Combination (95% Confidence Interval) of Fit (r²) 5-HT +WAY-100635 217.1 0.988 (127.4 to 369.7) Test compound + 392.2 0.989WAY-100635 (224.1 to 686.2)

1-8. (canceled)
 9. A method of treating a patient suffering from adisorder of the central nervous system, selected from (i) bipolar Idisorder with most recent mixed, depressed or unspecified episode, and(ii) bipolar II disorder with recurrent major depressive episodes withhypomanic episodes, the method comprises: administering to said patienta pharmaceutical composition comprising a therapeutically effectiveamount of a carbostyril compound of formula (1), or a pharmaceuticallyacceptable salt or solvate thereof, wherein said patient is a mammal:

wherein the carbostyril compound of formula (I) is both a partial D₂receptor agonist and a partial 5-HT_(1A) receptor agonist facilitatingtreatment of both mania and depression of bipolar I and bipolar IIdisorders, further wherein the compound of formula (I) is the onlyantipsychotic administered to said patient.
 10. The method of claim 9,wherein the disorder is bipolar I disorder as defined in (i).
 11. Themethod of claim 9, wherein the disorder is bipolar II disorder asdefined in (ii).
 12. The method according to claim 9, wherein thecarbostyril compound is7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxyl}-3,4-dihydrocarbostyril.13. The method according to claim 10, wherein the carbostyril compoundis7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxyl}-3,4-dihydrocarbostyril.14. The method according to claim 11, wherein the carbostyril compoundis7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxyl}-3,4-dihydrocarbostyril.